Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide. Untreated genital chlamydial infections cause serious sequelae such as pelvic inflammatory disease, ectopic pregnancy, and infertility. The mechanisms involved in the pathogenesis of chlamydial infections are not understood, and needs urgent attention to develop strategies to reduce the clinically highly relevant pathology induced by these infections. It is generally thought that the host immune response, primarily T cells, that are involved in clearance of the bacterium also cause collateral tissue damage and the pathological sequelae in the upper genital tract (UGT). We have recently found that mice depleted of CD8+ T cells display significantly reduced oviduct and uterine horn pathology, without a significant change in the kinetics of chlamydial clearance. Moreover, antigen-specific TNF-? production correlated with the development of chlamydial upper genital tract (UGT) pathology. An association between high levels of TNF-? production and chlamydial UGT pathology also has been suggested by other studies. Based on these results, we hypothesize that "Chlamydia-specific CD8? T cells mediate the upper genital tract pathology following primary genital chlamydial infection" and determine the role of TNF-? as an underlying mechanism. We will test this hypothesis by;(1) Examining the direct effect of adoptively transferred Chlamydia-specific CD8? T cells in the induction of chlamydial UGT pathology, including infertility, and (2) Examining the contribution of TNF-? as an underlying mechanism to the CD8+ T cell-mediated UGT pathology following primary genital chlamydial challenge. PUBLIC HEALTH RELEVANCE: Genital Chlamydia trachomatis infections lead to severe pathology in the upper genial tract including pelvic inflammatory disease, ectopic pregnancy, and infertility. We have observed that depletion of CD8+ T cells leads to significant reduction of chlamydial pathology in the mouse model of genital chlamydial infection. This proposal will further examine the contribution of CD8+ T cells in the induction of severe chlamydial upper genital tract pathologies, in an attempt to characterize a potential target for reduction of the clinically highly relevant pathologies. .